EP3873370A1 - Dispositifs de propulsion pour la propulsion à travers un milieu, à l'aide de stimuli magnétiques externes appliqués sur ceux-ci - Google Patents

Dispositifs de propulsion pour la propulsion à travers un milieu, à l'aide de stimuli magnétiques externes appliqués sur ceux-ci

Info

Publication number
EP3873370A1
EP3873370A1 EP19877808.6A EP19877808A EP3873370A1 EP 3873370 A1 EP3873370 A1 EP 3873370A1 EP 19877808 A EP19877808 A EP 19877808A EP 3873370 A1 EP3873370 A1 EP 3873370A1
Authority
EP
European Patent Office
Prior art keywords
magnet
biological
ranging
medium
propelling
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP19877808.6A
Other languages
German (de)
English (en)
Inventor
Michael Shpigelmacher
Alex Kiselyov
Hovhannes SARGSYAN
Suehyun CHO
John Caputo
Eli VAN CLEVE
Eran OREN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bionaut Labs Ltd
Original Assignee
Bionaut Labs Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bionaut Labs Ltd filed Critical Bionaut Labs Ltd
Publication of EP3873370A1 publication Critical patent/EP3873370A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B34/00—Computer-aided surgery; Manipulators or robots specially adapted for use in surgery
    • A61B34/70—Manipulators specially adapted for use in surgery
    • A61B34/72—Micromanipulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B34/00—Computer-aided surgery; Manipulators or robots specially adapted for use in surgery
    • A61B34/70—Manipulators specially adapted for use in surgery
    • A61B34/73—Manipulators for magnetic surgery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B34/00—Computer-aided surgery; Manipulators or robots specially adapted for use in surgery
    • A61B34/30—Surgical robots
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B34/00—Computer-aided surgery; Manipulators or robots specially adapted for use in surgery
    • A61B34/30—Surgical robots
    • A61B2034/302—Surgical robots specifically adapted for manipulations within body cavities, e.g. within abdominal or thoracic cavities
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B34/00—Computer-aided surgery; Manipulators or robots specially adapted for use in surgery
    • A61B34/30—Surgical robots
    • A61B2034/303—Surgical robots specifically adapted for manipulations within body lumens, e.g. within lumen of gut, spine, or blood vessels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B34/00—Computer-aided surgery; Manipulators or robots specially adapted for use in surgery
    • A61B34/70—Manipulators specially adapted for use in surgery
    • A61B34/73—Manipulators for magnetic surgery
    • A61B2034/731—Arrangement of the coils or magnets
    • A61B2034/733—Arrangement of the coils or magnets arranged only on one side of the patient, e.g. under a table

Definitions

  • micro robot also noted as “microbot”
  • microbot Controlled motion of a micro robot in a biologically or medically relevant environment depends on reliable external force, as well as on the properties of respective nano-/micro-particles of the microbot.
  • a propelling device and methods of use thereof are provided; the device is configured to propel through a medium, using external magnetic stimuli applied thereon; the device comprising: a propelling-element and a magnet in communication with the propelling element.
  • the magnet is configured to respond to the applied magnetic stimuli and to rotate the propelling- element; the propelling-element is configured to convert rotary motion thereof into translation motion, and thereby to propel the device through the medium.
  • a propelling device configured to propel through a medium, using external magnetic stimuli applied thereon, the device comprising:
  • the magnet is configured to respond to the applied magnetic stimuli and to rotate the helical element; and wherein the helical element is configured to convert rotary motion thereof into a translation motion along at least one of: the longitudinal axis, 2D trajectory, 3D trajectory; and thereby to propel the device through the medium.
  • the medium comprises at least one material selected from: viscoelastic medium, extracellular matrix, interstitial space, biological compartment, biological duct, biological vessel, biological node, biological tissue, biological organ;
  • the helical element comprises at least one material having Young’s modulus stiffness above 1 GPa, optionally selected from: Polypropylene, Polystyrene, high impact Polystyrene, Acrylonitrile butadiene styrene, Polyethylene terephthalate, Polyester, Polyamides (Nylons), Poly (vinyl chloride) (PVC), glass, ceramics, metals selected from: copper, bronze titanium, titanium related alloys, stainless steel, gold;
  • At least one nickel-plated neodymium optionally selected from: N35, N38, N40, N42, N45, N48, N50, N52, and N55; or
  • At least one alternative permanent nano/micro magnet material selected from: samarium cobalt (SmCo), alnico, ceramic, ferrite.
  • the front end of the helical element comprises a sharp and/or chiseled tip.
  • the magnet is accommodated at a front section, at a center section, or at a back section of the helical element.
  • the magnet is encased with a layer of titanium vessel.
  • the device is covered with- or embedded into a matrix that contains- an imaging agent, configured to facilitate visualization; the imaging agent optionally comprising at least one of: Rhodamine B, Fluorescein, microbubbles, microdefects, mesoporous silica nano- and micro- particles, and Upconversion Phosphors.
  • the imaging agent optionally comprising at least one of: Rhodamine B, Fluorescein, microbubbles, microdefects, mesoporous silica nano- and micro- particles, and Upconversion Phosphors.
  • the magnet is fixed to the helical element, optionally via an adhesive material comprising at least one of: epoxy, acrylics, polyurethane, UV curable, and cyanoacrylate based materials.
  • the adhesive material is incorporated with mesoporous nano- or micro- silica particles, configured to enhance contrast under ultrasound radiation.
  • the helical element comprises:
  • a propelling device configured to propel through a medium, using external magnetic stimuli applied thereon, the device comprising:
  • the magnet is accommodated at a front section or a back section of the cylindrical core.
  • magnet is configured to respond to the applied magnetic stimuli and to rotate the helical element; and wherein the screw-like element is configured to convert rotary motion thereof into translation motion along at least one of: the longitudinal axis, 2D trajectory, 3D trajectory; and thereby to propel the device through the medium.
  • the medium comprises at least one material selected from: viscoelastic medium, extracellular matrix, interstitial space, biological compartment, biological duct, biological vessel, biological node, biological tissue, biological organ;
  • the screw-like element comprises at least one material having Young’s modulus stiffness above 1 GPa, optionally selected from: Polypropylene, Polystyrene, high impact Polystyrene, Acrylonitrile butadiene styrene, Polyethylene terephthalate, Polyester, Polyamides (Nylons), Poly (vinyl chloride) (PVC), glass, ceramics, metals selected from: copper, bronze titanium, titanium related alloys, stainless steel, gold;
  • At least one nickel-plated neodymium optionally selected from: N35, N38, N40, N42, N45, N48, N50, N52, and N55; or
  • At least one alternative permanent nano/micro magnet material selected from: samarium cobalt (SmCo), alnico, ceramic, ferrite.
  • the screw-like element comprises:
  • a propelling device configured to propel through a medium, using external magnetic stimuli applied thereon, the device comprising: • a propelling element comprising:
  • a drill-bit-like element or a chisel-like configured to vacate the surrounding medium as it rotates through;
  • a screw-like element characterized by a cylindrical core and a helical ridge; or a twisted-ribbon-like element;
  • the diameter of the cylindrical magnet equals to- or smaller then- the outer diameter of the propelling element.
  • the magnet is attached to the back end of the propelling element via an adhesive material, optimally comprising at least one of: epoxy, acrylics, polyurethane, UV curable, and cyanoacrylate based materials.
  • the magnet is configured to respond to the applied magnetic stimuli and to rotate the propelling element; and wherein the propelling element is configured to convert rotary motion thereof into translation motion along at least one of: the longitudinal axis, 2D trajectory, 3D trajectory; and thereby to propel the device through the medium.
  • the medium comprises at least one material selected from: viscoelastic medium, extracellular matrix, interstitial space, biological compartment, biological duct, biological vessel, biological node, biological tissue, biological organ;
  • the propelling element comprises at least one material having Young’s modulus stiffness above 1 GPa, optionally selected from: Polypropylene, Polystyrene, high impact Polystyrene, Acrylonitrile butadiene styrene, Polyethylene terephthalate, Polyester, Polyamides (Nylons), Poly (vinyl chloride) (PVC), glass, ceramics, metals selected from: copper, bronze titanium, titanium related alloys, stainless steel, gold;
  • the magnet comprises: at least one nickel-plated neodymium optionally selected from: N35, N38, N40, N42, N45, N48, N50, N52, and N55; or
  • At least one alternative permanent nano/micro magnet material selected from: samarium cobalt (SmCo), alnico, ceramic, ferrite.
  • propelling element s outer diameter ranging between 0.5 - 1.5 mm;
  • propelling element s inner diameter ranging between 0.2 - 0.85mm;
  • propelling element’ s pitch ranging between 0.44 - 0.8lmm;
  • a propelling device configured to propel through a medium, using external magnetic stimuli applied thereon, the device comprising:
  • the magnet is configured to respond to the applied magnetic stimuli and to rotate the tube; and wherein the tube’s carved helical-like front section is configured to convert rotary motion thereof into translation motion along at least one of: the longitudinal axis, 2D trajectory, 3D trajectory; and thereby to propel the device through the medium.
  • the medium comprises at least one material selected from: viscoelastic medium, extracellular matrix, interstitial space, biological compartment, biological duct, biological vessel, biological node, biological tissue, biological organ;
  • the tube comprises at least one material having Young’s modulus stiffness above 1 GPa, optionally selected from: Polypropylene, Polystyrene, high impact Polystyrene, Acrylonitrile butadiene styrene, Polyethylene terephthalate, Polyester, Polyamides (Nylons), Poly (vinyl chloride) (PVC), glass, ceramics, metals selected from: copper, bronze titanium, titanium related alloys, stainless steel, gold;
  • At least one nickel-plated neodymium optionally selected from: N35, N38, N40, N42, N45, N48, N50, N52, and N55; or
  • At least one alternative permanent nano/micro magnet material selected from: samarium cobalt (SmCo), alnico, ceramic, ferrite.
  • a propelling device configured to propel through a medium, using external magnetic stimuli applied thereon, the device comprising:
  • the magnet is attached to the back end of the wedge-like- element via an adhesive material, optimally comprising at least one of: epoxy, acrylics, polyurethane, UV curable, and cyanoacrylate based materials.
  • the magnet is configured to respond to the applied magnetic stimuli and to translate the wedge-like-element, and thereby to propel the device through the medium.
  • the medium comprises at least one material selected from: viscoelastic medium, extracellular matrix, interstitial space, biological compartment, biological duct, biological vessel, biological node, biological tissue, biological organ;
  • the wedge-like element comprises at least one material having Young’s modulus stiffness above 1 GPa, optionally selected from: Polypropylene, Polystyrene, high impact Polystyrene, Acrylonitrile butadiene styrene, Polyethylene terephthalate, Polyester, Polyamides (Nylons), Poly (vinyl chloride) (PVC), glass, ceramics, metals selected from: copper, bronze titanium, titanium related alloys, stainless steel, gold;
  • At least one nickel-plated neodymium optionally selected from: N35, N38, N40, N42, N45, N48, N50, N52, and N55; or
  • At least one alternative permanent nano/micro magnet material selected from: samarium cobalt (SmCo), alnico, ceramic, ferrite.
  • Fig. 1 demonstrates an example for a propelling device having a helical spring-like element, according to various embodiments of the invention
  • Figs. 2A, 2B, 2C and 2D demonstrate four more examples for a propelling device having a helical spring-like element, according to various embodiments of the invention
  • Fig. 3 demonstrates an example for a propelling device comprising a screw-like element, according to various embodiments of the invention
  • Figs.4A, 4B, 4C and 4D demonstrate four examples for a propelling device having a magnet attached to a propelling element, according to various embodiments of the invention
  • Fig. 5 demonstrates another example for a propelling device having a magnet attached to a propelling element, according to various embodiments of the invention
  • Fig. 6 demonstrates an example for a propelling device having a carved helical section, according to various embodiments of the invention
  • Fig. 7 demonstrates an example for a propelling device having a wedge-like element, according to various embodiments of the invention.
  • Fig. 8 demonstrates an example for a method of inserting a propelling device into an anesthetized rat’ s liver, according to various embodiments of the invention
  • Fig. 9 demonstrates an example for a method and an apparatus configured for external stimuli and control of a propelling device, according to various embodiments of the invention.
  • Fig. 10 demonstrates an example for a use of the apparatus for external stimuli and control of a propelling device, according to various embodiments of the invention
  • Figs. 11A, 11B and 11C demonstrate test results for levels of representative liver enzymes (ALT, AST) at days 0, 1 and 14 post-treatment with SKC8 particle, according to various embodiments of the invention
  • Figs. 12A, 12B and 12C demonstrate test results for levels of representative liver enzymes (ALT, AST) at days 0, 1 and 14 post-treatment with Hovo2 particle, according to various embodiments of the invention
  • Figs. 13A, 13B, 13C, 13D and 13E demonstrate levels of representative liver enzymes (ALT, AST) at days 0, 1 and 14 post-treatment with Hovo2 particle and 20G needle, according to various embodiments of the invention
  • Figs. 14A, 14B, 14C and 14D demonstrate images of liver damage of rat treated with Hovo2 microbot taken at 1 hr, 3hr, 24 hr, and 14 days, respectively;
  • Figs. 15A and 15B demonstrate liver injury score, observed in all sample’s vs. time after treatment
  • Fig. 16 demonstrates ultrasound image of spring based microbot, processed using image tracking software
  • Fig. 17 demonstrates a retraction device, which uses an Eppendorf tube with an ND52 0.8 mm magnet located on the tip.
  • micro robot also noted as “microbot”
  • microbot Controlled motion of micro robot in a biologically or medically relevant environment depends on reliable external force, as well as on the properties of respective nano-/micro- particles of the microbot.
  • a platform for active and accurate delivery of microparticles is provided, endowed with diverse therapeutic load(s) and/or diagnostics to a specific location using external stimuli.
  • propelling devices and microbots will include particles described in International Patent Application PCT/US2018/030960 filed on May 3, 2018 and titled“METHODS AND SYSTEMS TO CONTROL PARTICLES AND IMPLANTABLE DEVICES,” which is hereby incorporated by reference in its entirety.
  • MEM microelectromechanical
  • propelling devices which comprise: (i) an actuator; (ii) a responsive element; (iii) a sensor; and (iv) an electronic circuit; wherein: said actuator controls and operates said responsive element; said electronic circuit controls said actuator; and said sensor receives signals transmitted by a remote unit.
  • propelling devices and microbots will be included in the platforms described in International Patent Application PCT/US2018/030960.
  • platforms comprise the following modules: (a) one or more propelling devices or microbots described herein and comprising embedded logic and various MEM components; (b) a delivery and/or retraction module, configured to deliver and/or retract the devices; (c) an external signal generator; (d) an imaging module, configured to monitor said particles; and (e) an integration module configured to receive inputs from and to provide output control commands to other modules; wherein: said modules are configured to interact/communicate with each other; and said modules are internally controlled, externally controlled or both; and wherein said platform provides active, pre-determined, fully controlled, precise delivery of said devices in vitro, in vivo, and/or in a patient.
  • Figs. 1, 2A, 2B, 2C and 2D demonstrate (helical)“spring based” propelling microbots, as provided according to some embodiments of the invention, which are configured to provide a corkscrew-like motion, thereby an effective propulsion motion through varying viscoelastic media.
  • a propelling device configured to propel through a medium, using external magnetic stimuli applied thereon, the device comprising:
  • the magnet is configured to respond to the applied magnetic stimuli and to rotate the helical element; and the helical element is configured to convert rotary motion thereof into a translation motion along at least one of: the longitudinal axis, 2D trajectory, 3D trajectory, and thereby to propel the device through the medium.
  • the medium (not shown), mentioned above and/or in the following, comprises at least one of: viscoelastic medium, extracellular matrix, interstitial space, biological compartment, biological duct, biological vessel, biological node, biological tissue, biological organ.
  • the front end of the helical element comprises a sharp and/or chiseled tip (112).
  • the magnet is accommodated at a center section of the helical element (as demonstrated in Figs 2A-2D), at a front section of the helical element (not shown), or at a back section of the helical element (as demonstrated in Fig. 1). It is noted that the terms“front” and“back” are relative to the designed motion direction of the microbot particle. According to some embodiments, the location and the length of the magnet is determined based on the medium to propelled in. According to some embodiments, the magnet is fixed to the helical element, optionally via an adhesive material. According to some embodiments, the adhesive material comprises at least one of: epoxy, acrylics, polyurethane, UV curable, and cyanoacrylate based materials.
  • the spring-based microbots provide efficient motion under ultrasonic images, due to the lack of its metallic components, their signal-to- noise ratio of ultrasonic responses may be improved. This may become problematic in vivo due to copious cavities present in organs of interest.
  • a solution is provided by incorporating various diameters of mesoporous silica particles into the spring-based microbots.
  • the adhesive material is incorporated with mesoporous nano- or micro- silica particles, configured to enhance contrast under ultrasound radiation. Therefore, a“sonic spring based” microbot is provided.
  • An example for fabricating such a sonic spring based microbot includes a fabrication process which is nearly identical to that of spring-based microbots described above.
  • Stainless steel micro-springs of inner diameters ranging from 0.4mm to l.lmm with wire diameters ranging from 0.l50mm to 0.255mm were extended with equal force on each end until the pitch of the spring was between 0.7mm and 1.5 mm. Then, an end of this extended spring was clipped off with a nipper plier. Afterwards, an N52 magnet was inserted within the extended spring and axially aligned with the spring. A few milligrams (mg) of mesoporous silica particles were mixed in with epoxy.
  • Fig. 2B demonstrates a typical sonic spring-based microbot. According to some further experiments, when the spring -based microbots were embedded with lpm mesoporous silica particles, there was a significant increase in brightness. This is due to the air-bubbles present in silica pore responding to the incident ultrasound.
  • the magnet in order to reduce variability in preparing the spring- based magnetic particles, microbots that do not require any adhesives, but fit snugly within the spring are provided herein.
  • the magnet is encased with a layer of titanium vessel, before it is inserted into the helical element.
  • Fig. 1 A non-limiting example is demonstrated in Fig. 1, showing an N52 magnet with an outer diameter of 0.5 millimeter (mm) and a length of 1 mm, which was encased in a thin layer of titanium vessel. Then, the titanium vessel containing the magnet was physically inserted inside the spring (110) with inner diameter of 0.61 mm and wire thickness (diameter) of 0.152 mm.
  • the no-adhesive spring -based microbots were examined in freshly euthanized rat liver in vivo to exhibit good mobility under rotating magnetic field gradient. Subsequently, single microbot, presented in Fig. 1, traversed through various liver sub-compartments of eight rats at magnetic field strength of -250 mT and a gradient of IOT/m without any damage or degradation.
  • the device is covered with- or embedded into a matrix that contains- an imaging agent, configured to facilitate its visualization ex vivo or in-vivo.
  • the imaging agent optionally comprises at least one of: Rhodamine B, Fluorescein, microdefects, microbubbles, microdefects, mesoporous silica nano- and micro particles, and Upconversion Phosphors.
  • the helical element comprises a material having Young’s modulus stiffness above 1 Giga Pascal ( GPa ), optionally selected from: Polypropylene, Polystyrene, high impact Polystyrene, Acrylonitrile butadiene styrene, Polyethylene terephthalate, Polyester, Polyamides (Nylons), Poly (vinyl chloride) (PVC), glass, ceramics, metals, titanium, titanium related alloys, stainless steel, gold.
  • Young’s modulus stiffness above 1 Giga Pascal ( GPa ) optionally selected from: Polypropylene, Polystyrene, high impact Polystyrene, Acrylonitrile butadiene styrene, Polyethylene terephthalate, Polyester, Polyamides (Nylons), Poly (vinyl chloride) (PVC), glass, ceramics, metals, titanium, titanium related alloys, stainless steel, gold.
  • the magnet (mentioned above and/or in the following) comprises:
  • At least one nickel-plated neodymium optionally selected from: N35, N38, N4Q, N42, N4S, N48, N50, N52, and N55; or
  • At least one alternative permanent nano/micro magnet material selected from: samarium cobalt (SmCo), alnico, ceramic, ferrite.
  • the helical element comprises:
  • outer diameter (113) ranging between 0.66 - 1.2 mm;
  • pitch (115) length ranging between 0.5 - 2.2mm
  • the magnet comprises:
  • outer diameter (124) ranging between 0.3 - 0.8mm
  • Examples for“spring-based” microbots Stainless steel micro-springs of inner diameters, ranging from 0.4mm to 1. lmm with wire diameters ranging from 0. l50mm to 0.255mm, were extended with equal force on each end until the pitch of the spring was between 0.7mm and 1.5 mm. Then, an end of this extended spring was clipped off with a nipper plier. This created a sharp and chiseled tip for the microbot. Afterwards, a nickel-plated neodymium 52 (N52) magnet of varying diameters and lengths (diameters ranging from 0.3mm to 0.8mm and lengths ranging from 0.5mm to 1.5 mm) were inserted within the extended spring and were axially aligned.
  • N52 nickel-plated neodymium 52
  • the distance from the edge of the magnet to the tip of the spring was measured to be between 0.3mm and 1.22 mm.
  • Figs. 2A and 2B are representative images of spring-based particles, where the magnet was affixed to the spring with cyanoacrylate and epoxy, respectively. It was demonstrated that microbots fixed with epoxy tend to have a more rounded body than those glued with cyanoacrylate.
  • imaging agents were incorporated onto the microbots.
  • the imaging agent e.g. Rhodamine B, Fluorescein, Upconversion Phosphors
  • Rhodamine B Fluorescein, Upconversion Phosphors
  • cyanoacrylate was deposited on top to seal the imaging agents to the magnet. This process was repeated three times and after the deposition of third layer, final layer of cyanoacrylate was deposited.
  • the imaging agents were added to the epoxy mixture and mixed in prior to applying it on the microbot.
  • Fig. 2C is a representative image of spring-based microbots that has been dusted with Rhodamine B prior to application of cyanoacrylate.
  • Fig. 2D shows a spring -based microbot that has been affixed with Rhodamine B-suspended epoxy. Particle propulsion was tested using both uniform (0.17) and gradient-based magnetic devices in order to select best performing system and particles.
  • Fig. 3 demonstrates a “screw-shaped” propelling microbot, provided according to some embodiments of the invention. According to some embodiments, this configuration closely mimics the shape of a screw, with a sharp tip and a base with constant pitch.
  • the screw-shape microbot configured to:
  • a propelling device (200) configured to propel through a medium, using external magnetic stimuli applied thereon, the device comprising:
  • a screw-like element characterized by a conical-core (not shown) or a cylindrical-core (211) and a helical ridge (212);
  • the magnet is accommodated at a back section of the cylindrical core.
  • the magnet is provided at a front section of the cylindrical core (not shown), in such embodiments, the length of the provided magnet is smaller than the length of the drilled hole.
  • the magnet is configured to respond to the applied magnetic stimuli and to rotate the helical element; and the screw-like element is configured to convert rotary motion thereof into translation motion along at least one of: the longitudinal axis, 2D trajectory, 3D trajectory; and thereby to propel the device through the medium.
  • the screw-like element comprises at least one material having Young’s modulus stiffness above 1 GPa, optionally selected from: Polypropylene, Polystyrene, high impact Polystyrene, Acrylonitrile butadiene styrene, Polyethylene terephthalate, Polyester, Polyamides (Nylons), Poly (vinyl chloride) (PVC), glass, ceramics, metals selected from: copper, bronze titanium, titanium related alloys, stainless steel, gold.
  • Young’s modulus stiffness above 1 GPa optionally selected from: Polypropylene, Polystyrene, high impact Polystyrene, Acrylonitrile butadiene styrene, Polyethylene terephthalate, Polyester, Polyamides (Nylons), Poly (vinyl chloride) (PVC), glass, ceramics, metals selected from: copper, bronze titanium, titanium related alloys, stainless steel, gold.
  • the screw-like element comprises:
  • outer diameter (216) ranging between 0.57 - 0.65mm
  • the hole diameter (219) ranging between 0.2 - 0.4mm.
  • the magnet (220) comprises:
  • outer diameter ranging between 0.2 - 0.5mm: length ranging between 0.5 - 1.5 mm.
  • Example for“screw-based” microbot A screw-like gold casing was fabricated with a length of 1.5 mm and total width (diameter) of 0.54mm. The pitch of the screw was measured to be 0.39mm. Afterwards, a small hole with a diameter of 0.3mm was drilled into the screw end. An N52 magnet with a diameter of 0.3mm and length of lmm was inserted into the hole. A representative image of such a screw-shaped microbot is provided in Fig. 3.
  • Figs. 4A-4D and Fig. 5 demonstrate propelling microbots comprising a magnet attached to a propelling element, provided according to some embodiments of the invention.
  • Microdrill bits are configured to provide a unique topology optimized to vacate the surrounding medium as they rotate through. Due to the limited inner diameter of the drill bit core, largest hole that can be drilled without compromising the integrity is about O.lmm, which may be too small to insert any magnets. Therefore, a provided solution is to attach a magnet at the base of the microdrill bit.
  • a propelling device (301,304,305), configured to propel through a medium, using external magnetic stimuli applied thereon, the device comprising:
  • a propelling element comprising:
  • a drill-bit-like element (Figs. 4A-4B, 310) or a chisel-like (not shown), configured to vacate the surrounding medium as it rotates through; or a screw-like element (Figs. 4C-4D, 330), characterized by a cylindrical core (338) and a helical ridge (339); or
  • a twisted-ribbon-like element (Fig. 5, 340); • a cube, cuboid, prism, ellipsoid, disc-like, cylindrical magnet (320), attached to the back end of the propelling element, wherein their longitudinal axes (314/334/344,324) are aligned.
  • the diameter (321) of the cylindrical magnet equals to- or smaller then- the outer diameter (311/331/341) of the propelling element.
  • the magnet is attached to the back end of the propelling element via an adhesive material, optimally comprising at least one of: epoxy, acrylics, polyurethane, UV curable, and cyanoacrylate based materials.
  • the magnet is configured to respond to the applied magnetic stimuli and to rotate the propelling element; and wherein the propelling element is configured to convert rotary motion thereof into translation motion along at least one of: the longitudinal axis, 2D trajectory, 3D trajectory; and thereby to propel the device through the medium.
  • the propelling element comprises at least one material having Young’s modulus stiffness above 1 GPa, optionally selected from: Polypropylene, Polystyrene, high impact Polystyrene, Acrylonitrile butadiene styrene, Polyethylene terephthalate, Polyester, Polyamides (Nylons), Poly (vinyl chloride) (PVC), glass, ceramics, metals selected from: copper, bronze titanium, titanium related alloys, stainless steel, gold.
  • Young’s modulus stiffness above 1 GPa optionally selected from: Polypropylene, Polystyrene, high impact Polystyrene, Acrylonitrile butadiene styrene, Polyethylene terephthalate, Polyester, Polyamides (Nylons), Poly (vinyl chloride) (PVC), glass, ceramics, metals selected from: copper, bronze titanium, titanium related alloys, stainless steel, gold.
  • the device (301,304,305) comprises:
  • propelling element s outer diameter (311,331,341) ranging between 0.5 - 1.5 mm; if relevant, propelling element’s inner diameter (312,332) ranging between 0.20 - 0.85mm;
  • the magnet (320) comprises:
  • N52 magnets with a diameter of 0.6 mm and length of 1 mm were attached to two different types of tips (propelling elements).
  • various configurations of microdrill bits were purchased and sent for post processing to laser-cut the drill bit tips to lengths of 2 mm.
  • a representative image of these microdrill tip is provided in Fig. 4A.
  • a second set of tips were fabricated to 1.5 mm long micro-screws with outer diameter of 0.75 mm and pitches of either 2 turns/mm or 3 turns/mm (Fig. 4C).
  • a piece of N52 magnet with an outer diameter of 0.6 mm and length of 1 mm was dipped into epoxy and was fixed to the base of either the microdrill bit tips and the micro-screw tips and held together by hand for a couple of minutes until they remained stationary. Afterwards, the microbots were left in air overnight for curing. Representative images of microbots fabricated with micro-drill bit tips and micro-screw tips are presented in Fig. 4B and Fig. 4D, respectively.
  • Fig. 6 demonstrates a“carved helix” propelling, provided according to some embodiments of the invention.
  • a hollow metal tube including but not limited to titanium and stainless steel
  • it allows one to control various physical parameters such as pitch and wire thickness.
  • the use of thicker helices provides more rigidity to the helices, thereby provides more support during propulsion.
  • a propelling device configured to propel through a medium, using external magnetic stimuli applied thereon, the device comprising:
  • the magnet is configured to respond to the applied magnetic stimuli and to rotate the tube; and wherein the tube’s carved helical-like front section is configured to convert rotary motion thereof into translation motion along at least one of: the longitudinal axis, 2D trajectory, 3D trajectory; and thereby to propel the device through the medium.
  • the tube comprises at least one material having Young’s modulus stiffness above 1 GPa, optionally selected from: Polypropylene, Polystyrene, high impact Polystyrene, Acrylonitrile butadiene styrene, Polyethylene terephthalate, Polyester, Polyamides (Nylons), Poly (vinyl chloride) (PVC), glass, ceramics, metals selected from: copper, bronze titanium, titanium related alloys, stainless steel, gold.
  • Young’s modulus stiffness above 1 GPa optionally selected from: Polypropylene, Polystyrene, high impact Polystyrene, Acrylonitrile butadiene styrene, Polyethylene terephthalate, Polyester, Polyamides (Nylons), Poly (vinyl chloride) (PVC), glass, ceramics, metals selected from: copper, bronze titanium, titanium related alloys, stainless steel, gold.
  • the tube comprises:
  • pitch (416) of the helical section ranging between 0.51 - l.50mm.
  • the magnet (420) comprises:
  • a carved-helix microbot is provided in Fig. 6, where an N52 magnet (hidden, 420) was inserted into the base of a metallic tube (410) with an inner diameter that matches the outer diameter of the magnet. Subsequently, the tip of the metallic tube was carved out (411) with a metal cutting device such as diamond tip cutter, laser, CNC tool, and other micro-cutting techniques to create helices.
  • a metal cutting device such as diamond tip cutter, laser, CNC tool, and other micro-cutting techniques to create helices.
  • a propelling device configured to propel through a medium, using external magnetic stimuli applied thereon, the device comprising:
  • the magnet is attached to the back end of the wedge-like- element via an adhesive material, optimally comprising at least one of: epoxy, acrylics, polyurethane, UV curable, and cyanoacrylate based materials.
  • the magnet is configured to respond to the applied magnetic stimuli and to translate the wedge-like-element, and thereby to propel the device through the medium.
  • the wedge-like element comprises at least one material having Young’s modulus stiffness above 1 GPa, optionally selected from: Polypropylene, Polystyrene, high impact Polystyrene, Acrylonitrile butadiene styrene, Polyethylene terephthalate, Polyester, Polyamides (Nylons), Poly (vinyl chloride) (PVC), glass, ceramics, metals selected from: copper, bronze titanium, titanium related alloys, stainless steel, gold.
  • Young’s modulus stiffness above 1 GPa optionally selected from: Polypropylene, Polystyrene, high impact Polystyrene, Acrylonitrile butadiene styrene, Polyethylene terephthalate, Polyester, Polyamides (Nylons), Poly (vinyl chloride) (PVC), glass, ceramics, metals selected from: copper, bronze titanium, titanium related alloys, stainless steel, gold.
  • the wide-like-element (520) comprises:
  • the magnet (520) comprises:
  • the above-mentioned magnets can comprise a cylinder, a ring, or a tube configuration. It is noted herein that when the“outer” diameter of the magnet is referred to, it may also refer to a cylinder’s diameter; or if the magnet’s diameter is mentioned, if relevant it may refer to the outer diameter.
  • Microbots dimension examples The above-mentioned propelling devices were test with various shapes and surfaces. Further, within same shape and surface properties, various dimensions were tested to demonstrate the effects that physical dimensions have on microbot mobility. Table 2 provides the dimension ranges per class of microbot.
  • the ability to deliver drugs through diverse heterogeneous tissue in a highly controlled and safe manner both spatially and longitudinally is anticipated to enhance safety-efficacy profile of multiple therapeutic agents and to address patient-specific conditions.
  • the focus of the currently provided technology is active and precise delivery of diverse therapeutics and/or diagnostics agents to a tissue of interest including liver.
  • the technology is likely to become a standalone approach or supplement the existing standards of care suitable for the treatment of localized conditions including but not limited to tumors, inflammation, chronic pain, eye and/or muscle degenerative disorders and bacterial infections.
  • a multimodal platform was developed that includes magnetic propulsion, versatile microparticles, imaging-/image- analysis and particle delivery and retraction modules.
  • the provided particle is capable of delivering diverse payloads including drugs and diagnostics, both small molecules and biologies to remote, hard to reach locations in the human body in a minimally invasive manner.
  • the currently provided microparticles can move with high degree of accuracy in a variety of biological media including liver, gastric, vitreous tissues and deliver diverse targeted payloads to treat affected areas of up to 7 cm 3 in volume using a single device.
  • HCC hepatocellular carcinoma
  • liver toxicity The examined data suggests that the currently provided particles traversed reliably, reproducibly and safely through the liver without causing general tissue damage. Longitudinal studies of the liver toxicity further indicate that both needle and microparticle treatment caused rapid and transient changes to the liver histology 3 hrs post-treatment. The pathology was dramatically reduced by day 7 and the liver tissue was completely recovered at day 14 post-treatment. These acute changes and recovery of the liver tissue by day 14 were further corroborated via measurements of representative blood biomarkers ALT and AST.
  • the primary purpose of the study was to evaluate the ability for the provided particle to move through a heterogeneous tissue (the liver) without causing non-transient toxicity.
  • organ/tissue of therapeutic interest e.g., liver
  • organ/tissue of therapeutic interest e.g., liver
  • tissue such as liver
  • c) Intra-hepatic Implantation of the particle Following anesthesia induction, a midline incision was made in the skin of the abdomen and a second incision was made into the peritoneal cavity using blunt scissors. Insertion and retraction of the particle was performed on the surgical table. A particle was inserted completely into either Right Medial Lobe or Left Lateral Lobe of the liver using plastic forceps.
  • Fig. 8 demonstrates particle insertion in the liver (right medial lobe) of anesthetized rat using plastic forceps. Needle (20G, ca. 0.91 mm outer diameter) puncture was used as a positive control to assess the liver damage. The puncture was performed via the open-wound procedure to emulate the particle insertion sequence or in situ through skin.
  • Figs. 9 and 10 demonstrate an external propulsion platform, based on rotating permanent magnets; demonstrated are: the rotating magnets’ set-up; the anesthetized animal; a platform for the animal: and an US probe.
  • the position of the rat was adjusted so that the inserted particle is facing the center of the magnet at a predetermined distance ( ⁇ 20 mm) using the proprietary fixed magnets platform (as in Figs. 9 and 10).
  • the particle was initiated and propelled using the external rotating magnets while being continuously observed as the device traversed the liver. Once the particle was ready to exit the liver as evidenced via visual observation, the rotating magnet was stopped.
  • Fig. 10 demonstrates relative position of the rat to the magnet; shown are: the surface of magnetic set-up, and approximate particle position.
  • the distance traveled by the particle in the liver was measured using calipers (5-8 mm on average).
  • the peritoneal cavity was closed post-procedure using nylon or polypropylene sutures.
  • the animal was returned to the individual cage to recover with ad libitum access to food and water. Generally, the recovery from anesthesia took 25-30 min. All animals were monitored every 15 min post-surgery for ca. 3hrs to ascertain overall well-being and normal physiological behavior. Notably, no animals were lost due to the procedure in either control (needle) or particle test groups. Moreover, all test animals seemed to have recovered completely within 1 hr post procedure.
  • Blood and liver tissue collection On Day 0, Day 1 and Day 14 post-procedure blood was collected by tail vein for measuring representative liver enzymes (ALT and AST, selected as dynamic markers based on the initial calibration studies). On Day 14, a specific liver tissue was collected (area traversed by the particle) for histology (H&E, hematoxylin and eosin staining).
  • H&E histology
  • liver tissue collection 1 hr, 3hrs, 2Ahrs and 14 days post-procedure, liver tissue (area traversed by the particle) was collected for histology (H&E, hematoxylin and eosin staining).
  • Results for diverse particles (SKC8 and Hovo2): In the toxicity assessment tests, several representative particles were used that illustrate at least two diverse designs including‘string based particle’ with a magnet accommodated in the center of the spring (SKC8), as demonstrated in Fig. 2C and‘spring based particle’ with a magnet accommodated in the back of the spring (Hovo2), as shown in Fig. 1. Particles design and dimensions are summarized in Table 5.
  • Figs. 11A-11C demonstrate levels of representative liver enzymes (ALT, AST) at days 0, 1 and 14 post-treatment with SKC8 particle; Fig. 11A demonstrates overall profile of liver enzymes, Figs. 11B and 11C demonstrate individual profile for the liver enzymes ALT and AST, respectively, where each differently colored circle represents an individual animal, N of 4 animals.
  • Figs. 12A-12C demonstrate test results for levels of representative liver enzymes (ALT, AST) at days 0, 1 and 14 post-treatment with Hovo2 particle; Fig. 12A demonstrates overall profile of liver enzymes; Figs. 12B and 12C demonstrate individual profile for the liver enzymes ALT and AST, respectively, where each differently colored circle represents an individual animal, N of 3 animals.
  • FIGS. 13B and 13C demonstrate individual profile for Hovo2 (ALT and AST, respectively); and Figs. 13D and 13E demonstrate individual profile for 20G needle group (where each differently colored circle represents individual animal, N of 5 for Hovo2 group and N of 3 for 20G needle group).
  • Figs. 14A-14D show images of liver damage of rat treated with Hovo2 microbot taken at Ali, 3 lv 24 hr, and 14 days respectively.
  • Figs. 15A and 15B demonstrate liver injury score, observed in all sample’s vs. time after treatment;
  • Fig. 15 A denotes injury score for animals treated with the Hovo2 microbot;
  • Fig. 15B denotes injury score for animals treated with a 20G needle.
  • the ultrasound-based visualization as potential imaging technique suitable to track the movement of the devices through tissue such as liver.
  • the tracking software takes a frame by frame comparison of the ultrasound video pixel by pixel to track the microbot. The comparison is made using color schemes in Python software environment via OpenCV. If there is a large difference with subsequent frame with the previous one at certain pixels, past a predetermined motion threshold, the code recognizes this as the robot in motion.
  • Fig. 16 demonstrates ultrasound image of spring based microbot, processed using image tracking software.
  • the retraction device uses an Eppendorf tube with an ND52 0.8 mm magnet located on the tip as demonstrated in Fig. 17 including the microbot retraction prototype device in the top left comer. The device was used successfully for in vivo retrieval of the particles post treatment experiments.

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Abstract

La présente invention concerne un dispositif de propulsion et leurs procédés d'utilisation. Le dispositif est conçu pour être propulsé à travers un milieu, à l'aide de stimuli magnétiques externes appliqués sur celui-ci; le dispositif comprend : un élément de propulsion et un aimant en communication avec l'élément de propulsion. L'aimant est conçu pour répondre aux stimuli magnétiques appliqués et pour faire tourner l'élément de propulsion; l'élément de propulsion est conçu pour convertir son mouvement rotatif en mouvement de translation, et ainsi propulser le dispositif à travers le milieu.
EP19877808.6A 2018-11-02 2019-10-31 Dispositifs de propulsion pour la propulsion à travers un milieu, à l'aide de stimuli magnétiques externes appliqués sur ceux-ci Withdrawn EP3873370A1 (fr)

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